WAC 2011 , Cancun

Dec. 6, 2011

Genetic susceptibility to Occupational asthma

Hae Sim Park, MD, Professor

Department of Allergy & Clinical Immunology

Ajou University School of Medicine,

Suwon, South Korea

Topics today …

1. HLA allele study

2. Candidate gene approach

3. Genome wide association studies

4. Gene to environmental interaction

LMW vs. HMW allergens

Isocyanate ( TDI / MDI) vs. wheat flour

/ lab animals

/digestive enzymes in health professionals

Occupational asthma : etiologies and risk factors

Vandenplas O, AAIR. 2011;3:157-67

.

Agent

Finland Canada, Quebec*

UK† France† South Africa†

Australia†

Belgium† B2elgium

*‡

Spain, Catalonia

† Korea*†

1995-2002

1995-1999

1996-2001

1996-1999

1997-1999

1997-1999

2000-2002

1998-2002

2002 1992-2006

Flour, cereals 17% 24% 9% 22% 12% 2% 13% 31% 10% 1%

Isocyanates 2% 18% 13% 14% 20% 6% 17% 15% 16% 50%

Latex

The pathogenic mechanisms of Isocyanate induced PA-complicated

Immune responses IgE/Th2 Response “ VAPOR” type IgG response

Genetic polymorphism /HLA allele DRB1*15-02 DRB1*0602 DPB1*0501 GSTP1, NAT2 , CTNNA3 ADRB2 46A>G

Autoimmune IgG to CK IgG to TG ase

Neurogenic ROS mediated

NK2R↔VEGF

Isocyanate -OA

Genetic interaction ADRB2 46 A>G

DQB1*0503(Asp) vs. DQB1*0501(Val) Bignon et al. Am J Respir Crit Care Med 1994;149:71-75,

Balboni et al. Eur Respir J 1996;9:207-210

DQA1*0104 and DQB1*0503 vs. DQA1*0101 and DQB1*0501

Mapp et al. Clin Exp Allergy 2000;30:651-656

DRB1*15-DPB1*05 haplotype Kim SH and Park HS et al. Allergy 2006;61:891-894

DRB1*1501-DQB1*0602-DPB1*05010.001(OR=7.235) Choi JH and Park HS et al. Int Arch Allergy Immunol, 2008

Association of HLA genes with TDI-OA

DP DQ DR A C B

Chromosome 6p Class II Class I Class III

Gene Full name Genotype Association Population

Genetic biomarkers

HLA Human leukocyte antigen DRB1*1501-DQB1*0602-DPB1* Yes Korean

HLA Human leukocyte antigen DQB1*0503 Yes European

HLA Human leukocyte antigen DQB1 *05 Yes Swedish

HLA Human leukocyte antigen DQB1*0501 No European

CTNNA3 Catenin alpha 3, alpha-T catenin HT2 [GG] Yes Korean

NK2R Neurokinin2 receptor 7853G>A, 11424 G>A Yes Korean

NAT1 N-acetyltransferase slow acetylator Yes Finnish

GSTP1 Glutathione transferase 105 Val Yes Swedish

NAT1 N-acetyltransferase NAT1*10 Yes Swedish

CCL5 Chemokine receptor -403 AG+AA Yes Swedish

Table . Genetic biomarkers for isocyanate-induced asthma

HLA; Human leukocyte antigen, CTNNA3; Catenin alpha 3, alpha-T catenin, NK2R; Neurokinin 2 receptor, NAT1; N-acetyl transferase, GSTP1; Glutathione transferase, CCL5; Chemokine receptor 5;AUC Area under curve

Palikhe N & Kim JH et al. AAIR 3:21-6 2011

Genome wide scan using Affymetrix 500 k Gene chip in TDI-OA

SNPchip

Fine-mapping

CTNNA3 was associated with

the phenotype of

TDI-OA

Kim SH et al. Clin Exp Allergy, 39:293, 2009

Loci

Genotype /Haplotype

IgE to TDI-HSA

p-value* OR (95% CI) positive negative

n=23 (%) n=117(%)

46 A>G (Arg16Gly)

AA 11(47.8) 22(20.8) 0.013 14.95(1.77-126.01)

AG 11(47.8) 55(51.9) 0.089 6.22(0.76-51.13)

GG 1(4.3) 29(27.4) R

252 G>A (Leu134Leu)

GG 12(52.2) 31(30.1) 0.045 8.87(1.05-74.93)

AG 10(43.5) 51(49.5) 0.166 4.51(0.53-38.12)

AA 1(4.3) 21(20.4) R

523 C>A (Arg175Arg)

CC 13(56.5) 29(28.2) 0.021 12.33(1.45-104.74)

AC 9(39.1) 51(49.5) 0.146 4.92(0.57-42.31)

AA 1(4.3) 23(22.3) R

ht1[TTACGC]

ht1/ht1 10(43.5) 20(18.7) 0.012 15.40(1.81-131.06)

ht1/- 12(52.2) 57(53.3) 0.078 6.60(0.81-53.73)

-/- 1(4.3) 30(28.0) R

ht2[TTGCAA]

ht2/ht2 1(4.3) 18(16.8) 0.064 0.13(0.02-1.13)

ht2/- 9(39.1) 55(51.4) 0.087 0.43(0.17-1.13)

-/- 13(56.5) 34(31.8) R

ADRB2 46 A>G polymorphism and specific IgE sensitization in TDI - exposed workers

.

Ye YM et al. AAIR 2:260, 2010

Baker’s Asthma

Exposed workers with respiratory symptoms

Exposed workers without respirotory symptoms

non-exposed workers

0.0

0.2

0.4

0.6

0.8

1.0

sIgG1 sIgG4

* *

* *

* pG AA (n=30)

ADRB2 46A>G AG or GG (n=79)

Exposure intensity

Hur GY et al. Resp Med J, 102:545, 2008

Fig. (A) Comparison of serum IL-8 level in the bakery workers and unexposed normal healthy controls. The mean value is indicated as horizontal line(). (B) Correlation between the serum levels of MPO and IL-8 in the bakery workers.

0

100

200

300

400

500

0 500 1,000 1,500 2,000

B

R=0.554 p

TLR4 -2026 A>G TLR4 -1607 T>C

AA+AG (%) GG (%) p TT+TC (%) CC (%) p

Work-related respiratory symptoms

Upper 104 (32.5) 19(32.8) 1.000 108 (31.2) 11 (39.3) 0.402

Lower 52 (16.1) 2 (3.4) 0.007 54 (15.5) 0 (0) 0.021

Positive skin prick test to wheat flour

22 (7.0) 1 (1.8) 0.226 22 (6.5) 0 (0) 0.395

Specific IgE to wheat flour

20 (6.2) 5 (8.6) 0.562 21 (6.0) 3 (10.7) 0.408

IL-8 (pg/ml)* 299.15±19.92 283.74±46.03 0.754 297.92±18.85 286.92±52.60 0.872

MPO (ng/ml)* 141.61±4.68 129.23±8.02 0.284 284.70±22.35 311.73±28.70 0.458

TLR4 polymorphism in bakers asthma

Cho HJ et al. Ann Allergy Asthma Immunol, 107:57, 2011

♣ LPS→TLR4→ Neutrophil activation in wheat flour

High molecular weights Drugs: digestive enzymes

Porcine extracts, empynase, Latex

Low molecular weights Antibiotics: cephalosporin, quinolone, piperacillin Cleaning and fixing agents

Occupational rhinitis

Occupational asthma

Allergic contact dermatitis

Acute urticaria

Anaphylaxis

Inhalation

Skin

The pathogenic mechanisms

Immediate (specific IgE) hypersensitivity reaction Delayed type hypersensitivity

Clinical features of occupational allergy in hospital personnel

Occupational Asthma

/ Rhinitis in HCW

Work-related Respiratory symptoms

Asymptomatic exposed workers

ADRB2 46A>G AA [p=0.023, OR=1.694(1.077-2.666)]

IL10-1082 A>G AG or GG [p=0.027, OR=2.251(1.2254.138)]

Total IgE, exposure intensity

Digestives Allergy Specific IgE to digestives : OR 5.70 (1.919~16.923)

SPT with digestives : OR 1.90 (0.865~4.179)

Risk factor for IgE sensitization to digestive enzymes in HCWs

Ye YM et al. Int Arch Allergy Immunol, 153:193, 2010

Perspectives

More efforts should be focused on developing early diagnostic genetic markers based on complicated pathogenic mechanisms of OA.

1

More efforts could be devoted for identifying asymptomatic sensitizers and occupational rhinitis, which are risk factors for OA.

2

We should set up a surveillance system to initiate the screening of OA patients using early diagnostic marker. If OA is suspected, we should refer the patients to a specialist to confirm OA.

3